Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[N:10]([O-])=O.[Na+].[Sn](Cl)Cl>O.Cl>[F:1][C:2]1[C:3]([CH3:9])=[C:4]([NH:5][NH2:10])[CH:6]=[CH:7][CH:8]=1
Reactant: O=N[O-]
Reactant: Cc1c(N)cccc1F
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: Cc1c(F)cccc1NN
Temperature: 0 °C
Reaction time: 1 h
Yield: 34.2 %

Procedure:
24 g 3-Fluoro-2-methyl-aniline was added to 120 ml 25% hydrochloric acid and the mixture cooled to 0° C. A solution of 15 g sodium nitrite in 80 ml water was added dropwise to the resulting suspension at such a rate that the temperature did not rise above 8° C. When the addition was complete, the mixture was stirred 1 h at 0° C. Whilst maintaining the mixture at 0° C., a suspension of 195 g tin (II) chloride in 230 ml 25% aqueous hydrochloric acid was added over 30 min. The mixture was stirred a further 20 min, and the precipitate that formed was filtered. The crude hydrochloride salt was partitioned between water and dichloromethane, and the pH raised to pH8 by the addition of sodium hydroxide solution followed by saturated sodium bicarbonate solution. The phases were separated, the aqueous phase extracted twice with dichloromethane and the combined organic phases dried over sodium sulfate and evaporated. The resulting solid residue was recrystallised from hexane to afford the title compound as a light brown solid (9.2 g, 34% yield, mp 69° C.; EI-MS m/e: 140.1 (M+)).
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]=[C:10]([CH2:12][CH2:13][O:14][C:15]3[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:24][NH:25][C:26]([NH2:28])=[O:27].CC([O-])=O.[Na+].O>CO>[C:1]1([C:7]2[O:8][CH:9]=[C:10]([CH2:12][CH2:13][O:14][C:15]3[CH:22]=[CH:21][C:18]([CH:19]=[N:24][NH:25][C:26]([NH2:28])=[O:27])=[CH:17][CH:16]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NNC(N)=O
Reactant: O=Cc1ccc(OCCc2coc(-c3ccccc3)n2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: NC(=O)NN=Cc1ccc(OCCc2coc(-c3ccccc3)n2)cc1
Temperature: 100 °C
Reaction time: 64 h
Yield: 89.2 %

Procedure:
A mixture of 20.0 g of aldehyde from Example 17 Part A, 8.29 g of semicarbazide hydrochloride, 8.14 g of NaOAc and 150 mL of H2O was heated for 0.75 hours at 100° C. with occasional swirling. The heterogenous mixture was diluted with 150 mL of MeOH and allowed to stand at 25° C. for 64 hours. The solid was filtered and washed with H2O, refluxed with 500 mL of MeOH and filtered hot leaving 21.3 g of 4-(2-(2-phenyl-4-oxazolyl)ethoxy)benzaldehyde semicarbazone (89%, m.p. 221°-226° C.).
Reaction SMILES: [H][H].Cl.[NH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][CH:11]=2)[CH2:6]1>>[C:7]1([CH:8]2[CH2:9][O:15]2)[CH:12]=[CH:13][CH:14]=[CH:5][CH:6]=1.[NH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][CH:11]=2)[CH2:6]1
Reactant: [H][H]
Agent: CCOC(=O)COc1ccc2c(c1)CC(N)CC2
Agent: Cl
Product: c1ccc(C2CO2)cc1

Procedure:
A solution of 27 g of 2-benzylamino-7-carbethoxymethoxytetraline hydrochloride, EXAMPLE 1, in 300 ml of 95% ethanol and 25 ml of water, is hydrogenated under ordinary pressure and at temperature of 50° C. by using 3 g of 10% palladium on charcoal as a catalyst. After 3 hours, the mixture is filtered, the residue is taken up twice with 100 ml of absolute ethanol and dried every time. The product so obtained is triturated in 150 ml of acetone, filtered and crystallized from 100 ml of isopropanol to give 19 g of 2-amino-7-carbethoxymethoxytetraline hydrochloride; m.p. 143°-145° C. The product thus obtained may be used for the preparation of the compound of formula (XV) above, in which X is hydrogen and O-R' is a carbethoxymethoxy group (COMPOUND 1), as follows: A solution of 1.8 g of phenyloxirane and 3.7 g of 2-amino-7-carbethoxymethoxytetraline base, obtained by neutralization of the hydrochloride described above, in 40 ml of n-butanol is heated under reflux for 6 hours. The mixture is concentrated to dryness, the residue is purified by flash chromatography, by eluting with a mixture of ethyl acetate/methanol 9/1. The purified oil is left to react overnight with an excess of oxalic acid in 5 ml of isopropanol. Thus, 1.9 g of N-(7-carbethoxymethoxy-1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-2-phenylethanamine oxalate is obtained; m.p. 159°-162° C., identical with the compound of Example 5 of the European patent 211 721.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:15][C:16]([NH2:18])=[O:17])=[CH:7]1>C(OC)(C)(C)C>[C:8]1([C:15]2[C:16](=[O:17])[NH:18][C:5](=[O:1])[C:4]=2[C:3]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[NH:6][CH:2]=2)[C:9]2=[C:14]3[C:13](=[CH:12][CH:11]=[CH:10]2)[CH2:15][CH2:8][CH2:7][N:6]3[CH:7]=1
Reactant: C1CCOC1
Reactant: NC(=O)Cc1c[nH]c2ccccc12
Solvent: COC(C)(C)C
Product: O=C1NC(=O)C(c2cn3c4c(cccc24)CCC3)=C1c1c[nH]c2ccccc12

Procedure:
In step 1 of scheme I, lilolidine (Compound 4), was treated with oxalylchloride to give the acyl chloride in methyl tert-butyl ether (MTBE) reaction solvent. The addition of methanol was sufficient to afford the intermediate ketoester, 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)oxoacetic acid methyl ester (Compound 5). In Step 2 of the reaction, Compound 5 and indole-3-acetamide (Compound 5a) were combined to produce 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrole-2,5-dione (Compound 6). As described in detail in the following examples, it is not necessary to isolate intermediate Compound 5 to produce Compound 6. A solvent swap from MTBE into tetrahydrofuran (THF) was necessary prior to conducting Step 2, since both 5 and 5a have very poor solubility in MTBE. Following the addition of Compound 5a to consume Compound 5 in THF in the presence of base, HCl was added to complete the reaction to afford crude Compound 6. Crude Compound 6 was then purified from DCM and heptane to afford Compound 6 of sufficient purity to proceed to the next step. A detailed description of this process is shown in Example 1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:23][O:24][C:25]1[C:26]([CH2:33]Cl)=[NH+:27][CH:28]=[CH:29][C:30]=1[O:31][CH3:32].[CH3:35]CN(C(C)C)C(C)C>CC#N>[C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:33][C:26]1[C:25]([O:24][CH3:23])=[C:30]([O:31][CH3:32])[CH:29]=[CH:28][N:27]=1)[CH2:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([CH3:35])=[CH:16][N:15]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc[nH+]c(CCl)c1OC
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1cccnc1CNCCCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CC#N
Product: COc1ccnc(CN(CCCCNC(=O)OC(C)(C)C)Cc2ncc(C)cc2C)c1OC

Procedure:
Using General Procedure A: Reaction of {4-[(3-methyl-pyridin-2-ylmethyl)-amino]-butyl}-carbamic acid tert-butyl ester, 3,4-dimethoxy-2-chloromethylpyridinium hydrochloride, DIPEA and KI in CH3CN gave {4-[(3,4-dimethoxy-pyridin-2-ylmethyl)-(3,5-dimethyl-pyridin-2-ylmethyl)-amino]-butyl}-carbamic acid tert-butyl ester as an oily residue. 1H NMR (CDCl3) δ 1.30-1.35 (m, 2H), 1.43 (s, 9H), 1.48-1.55(m, 2H), 2.14 (s, 3H), 2.27 (s, 3H), 2.95-3.00 (m, 2H), 3.76 (s, 6H), 3.91 (s, 3H), 5.14 (bs, 1H), 6.79 (d, 1H, J=6.9 Hz), 7.22 (s, 1H), 8.19 (s, 1H), 8.25 (d, 1H, J=6.9 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].C1C(=O)N([Br:19])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>FC(F)(F)C1C=CC=CC=1>[Br:19][CH2:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: FC(F)(F)c1ccccc1
Product: O=[N+]([O-])c1ccc(F)c(CBr)c1
Temperature: 25 °C
Yield: 84.6 %

Procedure:
A mixture of 2-fluoro-5-nitrotoluene (0.750 g, 4.83 mmol), NBS (1.549 g, 8.70 mmol) and AIBN (0.159 g, 0.967 mmol) in trifluorotoluene (15 ml) was heated to reflux overnight. The mixture was cooled RT, the solids removed via filtration and the filtrate concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford ˜80% pure 2-(bromomethyl)-1-fluoro-4-nitrobenzene (956 mg, 63% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7](OS(C)(=O)=O)[CH3:8].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]1[C:35](=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]1=[O:37])[CH3:21].CCN(C(C)C)C(C)C>CC#N.CN(C1C=CN=CC=1)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([N:22]([CH:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=1)[CH3:21])[CH2:23][CH2:24][CH2:25][CH2:26][N:27]1[C:35](=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]1=[O:37])[CH3:8]
Reactant: CC(OS(C)(=O)=O)c1ccccn1
Reactant: CC(NCCCCN1C(=O)c2ccccc2C1=O)c1ccccn1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(c1ccccn1)N(CCCCN1C(=O)c2ccccc2C1=O)C(C)c1ccccn1
Temperature: 60 °C
Reaction time: 17 h

Procedure:
Using General Procedure A: To a stirred solution of methanesulphonic acid 1-pyridin-2-yl-ethyl ester (269 mg, 1.34 mmol) and 2-[4-(1-pyridin-2-yl-ethylamino)-butyl]-isoindole-1,3-dione (356 mg, 1.10 mmol) in CH3CN (5 mL) at room temperature was added DIPEA (0.30 mL, 1.72 mmol) and KI (13 mg, 0.078 mmol). After 3 hours the temperature was increased to 60° C. and the mixture stirred for another 17 hours. KI (23 mg, 0.139 mmol) and DMAP (35 mg, 0.286 mmol) were added and the reaction stirred for a further 2 hours. Work up and purification by flash chromatography (35:1:1 CH2Cl2:MeOH:NH4OH) afforded pure 2-{4-[bis-(1-pyridin-2-yl-ethyl)-amino]-butyl}-isoindole-1,3-dione as a mixture of diastereomers (139 mg, 30%). 1H NMR (CDCl3) δ 1.18-1.49 (m, 10H) containing 1.27 (d, 3H, J=7.0 Hz) and 1.42 (d, 3H, J=7.1 Hz), 2.51-2.80 (m, 2H), 3.44-3.52 (m, 2H), 4.03-4.12 (m, 2H), 6.98-7.07 (m, 2H), 7.31 (d, 1H, J=7.9 Hz), 7.45-7.61 (m, 3H) containing 7.47 (d, 1H, J=7.9 Hz), 7.66-7.70 (m, 2H), 7.76-7.81 (m, 2H), 8.43-8.48 (m, 2H). ES-MS m/z 429 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[C:10](=[CH:16][N:17](C)C)[C:11]([O:13]CC)=O.[CH2:20]([NH:27][C:28](=[O:37])[C:29]1[CH:34]=[CH:33][C:32]([NH:35]N)=[N:31][CH:30]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([NH:27][C:28](=[O:37])[C:29]1[CH:34]=[CH:33][C:32]([N:35]2[C:11]([OH:13])=[C:10]([C:3]3[CH:4]=[CH:5][C:6]([C:8]#[N:9])=[CH:7][C:2]=3[Cl:1])[CH:16]=[N:17]2)=[N:31][CH:30]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)C(=CN(C)C)c1ccc(C#N)cc1Cl
Reactant: NNc1ccc(C(=O)NCc2ccccc2)cn1
Product: N#Cc1ccc(-c2cnn(-c3ccc(C(=O)NCc4ccccc4)cn3)c2O)c(Cl)c1

Procedure:
The title compound was prepared in a manner similar to Example 188 using ethyl 2-(2-chloro-4-cyanophenyl)-3-(dimethylamino)acrylate and N-benzyl-6-hydrazinylnicotinamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.44 (d, J=5.8 Hz, 2H) 7.13-7.22 (m, 2H) 7.27 (d, J=4.3 Hz, 5H) 7.75 (d, J=8.3 Hz, 1H) 8.00 (s, 1H) 8.30-8.47 (m, 2H) 8.90 (s, 1H) 9.20 (t, J=5.3 Hz, 1H). MS m/z [M+H]+ 430.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[C:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)=[C:7]2[CH3:24].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH3:37][O:38][C:39](=[O:42])[CH2:40]Br>O.C(O)(=O)C>[CH3:37][O:38][C:39](=[O:42])[CH2:40][O:25][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[C:11]2[C:6]=1[C:7]([CH3:24])=[C:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:16][CH:15]=1)[C:9](=[O:12])[NH:10]2
Reactant: Cc1c(Cc2ccc(S(C)(=O)=O)cc2)c(=O)[nH]c2c(Cl)ccc(O)c12
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccc(Cl)c2[nH]c(=O)c(Cc3ccc(S(C)(=O)=O)cc3)c(C)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 8-chloro-5-hydroxy-3-(4-methanesulfonylbenzyl)-4-methyl-1H-quinolin-2-one (0.20 g), N,N-dimethylformamide (4.0 mL), potassium carbonate (0.091 g) and bromoacetic acid methyl ester (0.079 g) was stirred at room temperature for 1 hour. The mixture was diluted with water (20 mL) and the pH adjusted to 4 by the addition of glacial acetic acid. The resulting precipitate was collected by filtration and purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (1:0 to 1:1 by volume) to afford title compound as a white solid, 0.14 g.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]2[C:10]=1[C:11](=[O:13])[CH3:12].C(O[CH:19](OC(C)(C)C)[N:20]([CH3:22])[CH3:21])(C)(C)C>CN1CCCC1=O>[Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]2[C:10]=1[C:11](=[O:13])/[CH:12]=[CH:19]/[N:20]([CH3:22])[CH3:21]
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Reactant: CC(=O)c1c(Cl)nc2ccccn12
Solvent: CN1CCCC1=O
Product: CN(C)/C=C/C(=O)c1c(Cl)nc2ccccn12

Procedure:
In a 100 mL round bottom flask, a solution of EXAMPLE 1C (4.25 g, 21.84 mmol), 1,1-di-tert-butoxy-N,N-dimethylmethanamine (28.8 mL, 120 mmol), and N-methyl-2-pyrrolidinone (15 mL) was heated at 85° C. for 2 hours. The reaction was concentrated under high vacuum on a rotavap at 60° C. The residual solid was triturated with 5 mL ether, filtered and dried to provide the title compound. MS (ES r) m/e 249.8 (M+H)+.
Reaction SMILES: [NH:1]=[C:2]([C:10]1[N:11]=[CH:12][N:13]2[C:18](=[O:19])[N:17]([CH3:20])[N:16]=[N:15][C:14]=12)[S:3][CH2:4][C:5](=O)[C:6]([OH:8])=O.ClC(OCC(C)C)=O.C(N(CC)CC)C.[CH2:36]([NH2:39])[C:37]#[CH:38]>C1COCC1>[CH3:20][N:17]1[C:18](=[O:19])[N:13]2[CH:12]=[N:11][C:10]([C:2]3[S:3][CH:4]=[C:5]([C:6]([NH:39][CH2:36][C:37]#[CH:38])=[O:8])[N:1]=3)=[C:14]2[N:15]=[N:16]1
Reactant: C#CCN
Reactant: Cn1nnc2c(C(=N)SCC(=O)C(=O)O)ncn2c1=O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#CCNC(=O)c1csc(-c2ncn3c(=O)n(C)nnc23)n1
Reaction time: 1 h
Yield: 36 %

Procedure:
To a solution of 3-(imino(3-methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazin-8-yl)methylthio)-2-oxopropanoic acid (0.65 g; 2.2 mmol) in dry THF (30 mL) under nitrogen was added isobutyl chloroformate (0.60 mL; 4.4 mmol), followed by triethylamine (0.62 mL; 4.4 mmol). The mixture was stirred for 1 hour, and then propargylamine (0.28 mL; 4.4 mmol) was added, and stirring continued for a further 3 hours. The precipitate was washed with water (5×15 mL) and diethyl ether (2×15 mL) to yield the title compound as a pale yellow solid (0.250 g; 36%). δH (DMSO-d6) 3.13 (1H, m), 3.89 (3H, s), 4.10 (2H, m), 8.47 (1H, s), 8.68 (1H, t, J=5.9), 8.95 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[O:20][CH2:21][C:22]([F:25])([F:24])[F:23])[CH2:5][N:6]1C(=O)C2C(=CC=CC=2)C1=O.CCCCCCCCCCCCN>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][NH2:6])[CH:17]=[CH:18][C:19]=1[O:20][CH2:21][C:22]([F:24])([F:25])[F:23]
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(OCC(F)(F)F)c(Cl)c1
Agent: CCCCCCCCCCCCN
Product: Cl
Product: NCc1ccc(OCC(F)(F)F)c(Cl)c1
Yield: 89 %

Procedure:
The title compound is prepared in 89% yield (593 mg, an off-white solid) from 2-(3-chloro-4-(2,2,2-trifluoroethoxy)benzyl)isoindoline-1,3-dione (890 mg, 2.41 mmol, Step-2) in a similar manner to Step-5 of Amine-12.
Reaction SMILES: C([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])C.[NH2:8][C:9]1[CH:10]=[C:11]([C:15]2[C:16](=[O:22])[N:17]([CH3:21])[CH2:18][C:19]=2[OH:20])[CH:12]=[CH:13][CH:14]=1.[CH3:23][N:24]([CH3:27])[CH:25]=[O:26]>>[CH2:11]1[CH2:12][CH:5]([C:4]2([NH:17][C:16]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]4[C:16](=[O:22])[N:17]([CH3:21])[CH2:18][C:19]=4[OH:20])[CH:10]=3)=[O:22])[N:3]=[CH:6][C:7]3[CH:13]=[CH:14][CH:9]=[CH:10][C:23]=3[N:24]([CH3:27])[C:25]2=[O:26])[CH2:18][CH2:19][CH2:15]1
Reactant: CN1CC(O)=C(c2cccc(N)c2)C1=O
Reactant: CN(C)C=O
Reactant: CCN(CC)CC
Product: CN1CC(O)=C(c2cccc(NC(=O)NC3(C4CCCCC4)N=Cc4ccccc4N(C)C3=O)c2)C1=O
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 30 %

Procedure:
A solution of 5-cyclohexyl-l,3-dihydro-1-methyl-3(R,S)-[(4-nitrohenyloxycarbonyl)amino]-2H-1,4-benzodiazepin-2-one (Example 1, Step 9) (400 mg, 0.92 mmol) in anhydrous dimethylformamide (5.5 ml), under an atmosphere of nitrogen, at ambient temperature, was treated with triethylamine (126 μl 0.92 mmol). After stirring for 5 min, a solution of 3-(3-aminophenyl)-1,5-dihydro-4-hydroxy-N-methyl-2H-pyrrol-2-one (187 mg, 0.92 mmol) in anhydrous dimethylformamide (5.5 ml) was added dropwise. The solution was then heated at 50° C. for 2 h. The solution was cooled to room temperature and the solvent evaporated in vacuo. The residue was partitioned between ethyl acetate (20 ml) and 20% aqueous acetic acid (20 ml). The undissolved solid was filtered off and triturated with ether (20 ml) then hot methanol (20 ml), to afford the title compound (139 mg, 30%) as a white solid. mp 199°-201° C. 1H NMR (360MHz, D6 -DMSO) δ0.91 (1H, m), 1.09-1.93 (9H, m), 2.90 (4H, m), 3.31 (3H, s), 3.91 (2H, s), 5.07 (1H, d, J=8Hz), 7.13 (1H, t, J=8Hz), 7.23 (1H, d, J=8Hz), 7.36 (2H, m), 7.54 (2H, m), 7.63 (1H, m), 7.75 (1H, d, J=8Hz), 7.84 (1H, s), 8.96 (1H, s).
Reaction SMILES: [C:1]([CH:3]([C:8]1[C:16]([O:17][CH3:18])=[CH:15][C:14]([CH3:19])=[C:13]2[C:9]=1[CH:10]=[CH:11][N:12]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:4]([O:6][CH3:7])=[O:5])#[N:2].IC.[C:29](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([C:3]([C:8]1[C:16]([O:17][CH3:18])=[CH:15][C:14]([CH3:19])=[C:13]2[C:9]=1[CH:10]=[CH:11][N:12]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH3:29])[C:4]([O:6][CH3:7])=[O:5])#[N:2]
Reactant: COC(=O)C(C#N)c1c(OC)cc(C)c2c1ccn2C(=O)OC(C)(C)C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)C(C)(C#N)c1c(OC)cc(C)c2c1ccn2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
(±)-tert-Butyl 4-(1-cyano-2-methoxy-2-oxoethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 155-C) (1.1 g, 3.07 mmol) was dissolved in acetone (6.14 ml) and then added iodomethane (0.576 ml, 9.21 mmol) followed by potassium carbonate (0.636 g, 4.60 mmol) and stirred at room temperature for 2.5 hours. The reaction was then cooled in an ice bath and quenched with a saturated aqueous solution of ammonium chloride and diluted with DCM. The layers were separated and the organic layer was dried and concentrated to obtain the title compound. MS (ESI+) m/z 373.4 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:18]([O:20]C)=[O:19])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.[Li+].[OH-].O.Cl>CO>[NH2:1][C:2]1[C:3]([C:18]([OH:20])=[O:19])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][N:7]=1
Reactant: COC(=O)c1nc(-c2ccc(S(C)(=O)=O)cc2)cnc1N
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)c1ccc(-c2cnc(N)c(C(=O)O)n2)cc1
Temperature: 90 °C
Yield: 99.4 %

Procedure:
A mixture of methyl 3-amino-6-(4-(methylsulfonyl)phenyl)pyrazine-2-carboxylate (3.50 g, 11.39 mmol) and LiOH (1.364 g, 56.95 mmol) was dissolved in Methanol (14 mL) and water (14 ml) and allowed to heat at 90° C. for 2 hours. The reaction mixture was allowed to cool and neutralized with 1M HCl. The resultant precipitate was collected by filtration to afford the pure product as a yellow solid (3.32 g, 99% Yield). MS (ES+) 293
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([O:26]C)=O)=[CH:15][C:13]=2[N:14]=1.[F:28][C:29]([F:38])([F:37])[C:30]1[N:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=1.C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:22])([CH3:23])[O:21][C:17]=3[C:16]([C:24]([NH:36][C:33]3[CH:34]=[N:35][C:30]([C:29]([F:38])([F:28])[F:37])=[CH:31][CH:32]=3)=[O:26])=[CH:15][C:13]=2[N:14]=1
Reactant: Nc1ccc(C(F)(F)F)nc1
Reactant: COC(=O)c1cc2nc(Nc3c(F)cccc3Cl)[nH]c2c2c1OC(C)(C)C2
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC1(C)Cc2c(c(C(=O)Nc3ccc(C(F)(F)F)nc3)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Yield: 9.8 %

Procedure:
The title compound was prepared by following the procedure described for Example-137 by using methyl 2-[(2-chloro-6-fluorophenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylate (Step-1 of Intermediate-15, 0.100 g, 0.256 mmol), 6-(trifluoromethyl)pyridin-3-amine (0.062 g, 0.387 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL), dry toluene (5.0 mL) to afford 0.013 g of the desired product. 1HNMR (DMSO-d6): δ 1.58 (s, 6H), 3.33 (s, 2H), 7.33-7.41 (m, 4H), 7.89 (d, J=9.0 Hz, 1H), 8.47 (d, J=6.6 Hz, 1H), 9.00 (s, 1H), 10.09 (s, 1H), 11.20 (br s, 2H); MS [M+H]+: 520.11
Reaction SMILES: CO[CH:3]([O:17]C)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[C:5]=1Br.[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][CH3:32])[CH:25]=O)[CH3:20].[C:33]([C:39]([O:41][CH3:42])=[O:40])#[C:34][C:35]([O:37][CH3:38])=[O:36]>>[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([C:25]2[C:5]3[C:4](=[CH:9][C:8]([O:10][CH3:11])=[C:7]([O:12][CH3:13])[C:6]=3[O:14][CH3:15])[C:3]([OH:17])=[C:34]([C:35]([O:37][CH3:38])=[O:36])[C:33]=2[C:39]([O:41][CH3:42])=[O:40])[CH:27]=[CH:28][C:29]=1[O:30][CH2:31][CH3:32])[CH3:20]
Reactant: CCOc1ccc(C=O)cc1OCC
Reactant: COC(=O)C#CC(=O)OC
Reactant: COc1cc(C(OC)OC)c(Br)c(OC)c1OC
Product: CCOc1ccc(-c2c(C(=O)OC)c(C(=O)OC)c(O)c3cc(OC)c(OC)c(OC)c23)cc1OCC

Procedure:
2-Bromo-3,4,5-trimethoxybenzaldehyde dimethylacetal, 3,4-diethoxybenzaldehyde and dimethyl acetylenedicarboxylate are treated in the same manner as described in Example 1-(1) and (2), whereby 1-(3,4-diethoxyphenyl)-2,3-bis(methoxycarbonyl)-4-hydroxy-6,7,8-trimethoxynaphthalene is obtained as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C@@H:5]([NH2:20])[C:6]1[CH:11]=[CH:10][C:9]([NH:12]C(OC(C)(C)C)=O)=[CH:8][CH:7]=1.[C:22](OC)(=[O:29])[CH2:23][CH2:24][CH2:25][C:26]([O-:28])=[O:27].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C@@H:5]([NH:20][C:22](=[O:29])[CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])[C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[CH:10][CH:11]=1
Reactant: COC(=O)CCCC(=O)[O-]
Reactant: COC(=O)C[C@@H](N)c1ccc(NC(=O)OC(C)(C)C)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C[C@@H](NC(=O)CCCC(=O)O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (R)-3-amino-3-[4-(tert-butoxycarbonylamino)phenyl]-propanoic acid methyl ester [1.5 g, Reference Example 7(c)], mono-methyl glutarate (0.7 ml), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (2.05 g), diisopropylethylamine (1.8 ml) and dimethylformamide (40 ml) was stirred at ambient temperature for 18 hours. The reaction mixture was evaporated to dryness and diluted with water (75 ml) and the resultant mixture acidified to pH1.0 by addition of concentrated hydrochloric acid. The mixture was extracted twice with ethyl acetate (75 ml). The combined extracts were washed with water (75 ml) then dried over magnesium sulphate and then evaporated. The resulting waxy fawn solid (3.8 g) was dissolved in dichloromethane (20 ml), cooled to 0° C., and the solution treated with trifluoracetic acid (4 ml). After stirring at ambient temperature for 2 hours the reaction mixture was evaporated and the residue taken up in ethyl acetate (50 m). The resultant solution was treated with ice cold saturated aqueous potassium carbonate solution (20 ml) with stirring at ambient temperature for 5 minutes. The organic layer was separated, washed with water (30 ml), dried over magnesium sulphate, and then evaporated to give (R)3-(4-carboxybutanoyl-amino)-3-(4-aminophenyl)-propanoic acid methyl ester (1.32 g) as a yellow oil.